Identification of 1,3-diiminoisoindoline carbohydrazides as potential antimalarial candidates.

TitleIdentification of 1,3-diiminoisoindoline carbohydrazides as potential antimalarial candidates.
Publication TypeJournal Article
Year of Publication2012
AuthorsMombelli P, Witschel MC, van Zijl AW, Geist JG, Rottmann M, Freymond C, Röhl F, Kaiser M, Illarionova V, Fischer M, Siepe I, Schweizer BW, Brun R, Diederich F
Date Published2012 Jan 2

A series of inhibitors of plant enzymes of the non-mevalonate pathway from herbicide research efforts at BASF were screened for antimalarial activity in a cell-based assay. A 1,3-diiminoisoindoline carbohydrazide was found to inhibit the growth of Plasmodium falciparum with an IC(50) value <100 nM. Synthesis of a variety of derivatives allowed an improvement of the initial antimalarial activity down to IC(50) =18 nM for the most potent compound, the establishment of a structure-activity relationship, and the evaluation of the cytotoxic profile of the diiminoisoindolines. Furthermore, interesting configurational and conformational aspects for this class of compounds were studied by computational and X-ray crystal structure analysis. Some of the compounds can act as tridentate ligands, forming 2:1 ligand-iron(III) complexes, which also display antimalarial activity in the nanomolar IC(50) range, paired with low cytotoxicity.

Alternate JournalChemMedChem